Hypertrophic cardiomyopathy (HCM) is a relatively common, globally distributed, and often hereditary primary heart disease (1), resulting in left ventricular hypertrophy, interstitial fibrosis, impaired ventricular filling, and left ventricular diastolic compliance (2, 3). HCM is a heterogeneous disease with various clinical manifestations, including heart failure (HF), arrhythmias, sudden cardiac death, and thromboembolism (4). Ischemic stroke (IS) is a catastrophic thromboembolic complication of HCM with aging (5, 6), as a previous study reported that the overall incidence of stroke or other vascular events in HCM patients was 0.8%/year and 1.9% for patients >60 years old (7). However, the risk factors, clinical characteristics, and prognosis of HCM complicated with IS remain largely unclear. Hence, we conducted a single-center retrospective study to investigate the risk factors, clinical characterizations of HCM-IS, and a 1-year follow-up to examine the short-term survival rate.

As a catastrophic adverse event, thromboembolism events (stroke and systemic embolic events) have a high incidence or prevalence in HCM patients worldwide, eventually contributing to increased morbidity and mortality (4, 9–12). To date, several risk factors for thromboembolism have been confirmed in HCM patients, including atrial fibrillation (AF), age, left atrial diameter, and HF. In the present study, we found that among all HCM patients, there were significant differences in age (≥63 years), type 2 diabetes, eGFR, and D-dimer levels between patients complicated with IS and those without IS. Furthermore, a multiple regression analysis revealed that age was an independent risk factor for the occurrence of IS in HCM. Consistent with the findings of two distinct retrospective studies (7, 13), our results indicate that a higher risk of IS is associated with older age in HCM patients. The explanation for this is that the abnormal morphology and function of the left atrial appendage render HCM patients prone to developing thromboembolic events since elderly patients have a higher incidence of abnormal cardiac structure and function (14). Additionally, as age increases, other cardiogenic or non-cardiogenic complications, such as hypertension, hyperlipidemia, diabetes, deep vein thrombosis, and AF, may increase the incidence of IS and affect long-term stroke outcomes in HCM patients (15–18). Hence, risk factor screening and early intervention should be performed routinely on elderly patients with HCM to prevent the occurrence of IS.

AF is the most common arrhythmia in HCM patients and is associated with a high risk of thromboembolism (19). In a Korean population–based study, the prevalence of stroke among HCM patients with AF was 20%, two times higher than the prevalence in all HCM patients (9). However, our study found no obvious association between AF and the risk of IS in HCM patients, possibly due to the relatively small number of HCM patients with AF. Interestingly, a recent large-scale study on HCM patients without AF (n = 17,371) found that their risk of IS was similar to that of controls from the general population with AF taking oral anticoagulants, indicating that HCM could carry a similarly high risk of thromboembolism as AF. The plausible explanation is that aging and other cardiovascular diseases can cause atrial cardiomyopathy, which in turn causes AF and thromboembolism (20). Evidently, our study demonstrated a significant association of older age with the higher risk of IS in HCM patients, mainly in the absence of AF. Nevertheless, more evidence is needed to address this issue in the future.

As one of the common complications of HCM, the risk of thromboembolism (IS and systemic embolism) is high in HCM patients mainly due to AF, as well as older age and left atrial dilatation (11, 21, 22). In our study, according to the TOAST classification, CE and SAO stroke constituted most HCM cases, particularly the former, revalidating that thromboembolism underlies the pathogenesis of IS. Notably, for the first time, our study reported brain neuroimaging characteristics of patients with HCM complicated by IS, such as multiple infarcts distributed in the cerebral cortex and subcortical region, as well as multi-vessel involvement, almost in line with the neuroimaging profile of cardiogenic stroke (23). However, considering the small sample size, further studies with larger sample sizes should be performed to confirm our results.

Previous studies have reported a high annual mortality rate of 3–6% among HCM patients worldwide (24–27), and the leading cause of death included sudden death and HF complications (28, 29). With the advancement of treatment methods over the past few decades, the prognosis for HCM has greatly improved, with an overall annual mortality rate of < 1% (13, 30–34). In the present study, the mortality rate for HCM patients was 8% during a 1-year follow-up period, and progressive HF and acute coronary syndrome were the leading causes of death. Compared to patients without IS, the proportion of adverse outcomes in patients with IS was relatively higher, implying that IS is the main cause of the increased mortality rate of HCM. Furthermore, Cox multivariate analysis revealed that IS, as a complication of HCM, was an independent risk factor for all-cause death in HCM patients, thus reconfirming our viewpoint to a large extent. Consistent with this, several studies have reported that stroke and peripheral embolism, two severe complications of HCM, may cause more disability and death in the elderly, particularly those over the age of 60 (7, 15). Hence, a detailed clinical evaluation and timely intervention should be conducted in HCM patients complicated with IS, especially the elderly, to improve the prognosis of HCM as much as possible.

The role of inflammation in IS has drawn great attention since neuronal death caused by occlusion of cerebral blood flow can trigger both local and systemic immune responses (35, 36). Accordingly, individuals with signs of inflammation or corresponding biomarkers have an increased risk of stroke (37). Of them, atherosclerosis, a well-known chronic inflammatory disease, can cause heart attack and ischemic stroke in the advanced stage (38). Notably, increased aortic pulse wave velocity (aPWV), an independent cardiovascular risk factor representing aortic stiffness, was found to be associated with inflammation (39), thereby indicating the potential clinical use of the measure of aPWV in IS. Nevertheless, the exact relationship between this parameter and HCM complicated with IS needs to be further ascertained.

In conclusion, we found that in HCM patients with IS, an older age (≥63 years) is a risk factor for the occurrence of stroke. In the classification of TOAST, CE and SAO subtypes predominate in patients with concomitant IS, especially the former. The IS patients had mild or moderate neurologic deficit at disease onset. Multiple, cortical, and subcortical infarctions are their neuroimaging characteristics, mainly involving the anterior circulation or anterior + posterior circulation. HCM patients complicated by IS have good short-term survival, and IS is a risk factor for all-cause deaths among HCM patients within 1 year. These findings will help neurologists and cardiologists identify HCM patients at high risk for IS and prevent its occurrence. However, our study has some limitations. First, because this was a single-center retrospective study, a significant bias could be produced by the incomplete clinical and imaging data (cardiac MRI, clinical evaluation after treatment, etc.); Second, an obvious limitation of this study is its lack of statistical power due to the small sample size, so the findings should be interpreted with high caution. Finally, the follow-up time was relatively short for most patients. Therefore, future multi-center, prospective studies using a larger sample size will help validate our findings' reliability and provide valuable new evidence for preventing and treating IS in HCM patients.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by Research Ethical Committee of Beijing Anzhen Hospital. The patients/participants provided their written informed consent to participate in this study.

G-ZL conceived the experiments, J-FL, Z-XF, and YL conducted the experiments. Z-YW, LM, B-YY, T-TY, and P-JL analysed the results. All authors contributed to the article and approved the submitted version.